# US 11,111,254 B2 · Nitrogen-containing macrocyclic conjugates as radiopharmaceuticals

> Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt

- Number: US 11,111,254 B2
- Document ID: US11111254B2
- Status: Granted
- Kind: B2
- Application number: 16/712,485
- Filed: 2019-12-12
- Published: 2020-04-16
- Granted: 2021-09-07
- Earliest claimed: 2008-12-02
- Assignees: The University of Melbourne
- Applicants: The University of Melbourne
- Inventors: Paul Stephen Donnelly; Michelle Therese Ma; Denis Bernard Scanlon
- Web page: https://patentgrep.com/patent/US11111254B2

## CPC

- C07D 521/00: Heterocyclic compounds containing unspecified hetero rings
- A61K 51/0482: {chelates from cyclic ligands, e.g. DOTA}
- A61K 51/082: {the peptide being a RGD-containing peptide}
- A61K 51/088: {conjugates with carriers being peptides, polyamino acids or proteins (antibodies A61K51/10)}
- A61P 35/00: Antineoplastic agents
- A61K 49/06: Nuclear magnetic resonance [NMR] contrast preparations; Magnetic resonance imaging [MRI] contrast preparations
- A61K 49/08: characterised by the carrier
- A61K 49/10: Organic compounds
- A61K 49/101: {the carrier being a complex-forming compound able to form MRI-active complexes with paramagnetic metals}
- A61K 51/00: Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K 51/02: characterised by the carrier {, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus}
- A61K 51/04: Organic compounds
- A61K 51/08: Peptides, e.g. proteins {, carriers being peptides, polyamino acids, proteins}
- A61K 51/10: Antibodies or immunoglobulins; Fragments thereof {, the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody}
- A61K 51/106: {the tumor cell being from kidney or bladder}
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present invention relates to compounds that are useful as metal ligands and which either contain a molecular recognition moiety or can be bound to a molecular recognition moiety and methods of making these compounds. Once the compounds that contain a molecular recognition moiety are coordinated with a suitable metallic radionuclide, the coordinated compounds are useful as radiopharmaceuticals in the areas of radiotherapy and diagnostic imaging. The invention therefore also relates to methods of diagnosis and therapy utilising the radiolabelled compounds of the invention.

## Claims

### Claim 1

A compound of formula (I),
wherein:
L is a nitrogen-containing macrocyclic metal ligand of the formula
V is selected from the group consisting of N and CR4;
each Rx and Ry are independently selected from the group consisting of H, CH3, CO2H, NO2, CH2OH, H2PO4, HSO3, CN, CONH2 and CHO;
each p is independently an integer selected from the group consisting of 2, 3, and 4; R4 is selected from the group consisting of H, OH, halogen, NO2, NH2, optionally
substituted C1-C12alkyl, optionally substituted C6-C-18aryl, cyano, CO2R5, NHR5, N(R5)2 and a group of the formula:
wherein
X1 is a linking moiety;
Y1 is selected from the group consisting of OR6, SR7, N(R8)2 and a molecular recognition moiety;
wherein R5 is H or C1-C12alkyl;
R6 is selected from the group consisting of H, halogen, an oxygen protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl;
R7 is selected from the group consisting of H, halogen, a sulfur protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C-12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl;
each R8 is independently selected from the group consisting of H, a nitrogen protecting group, optionally substituted C1-C12alkyl, optionally substituted C2-C12alkenyl, optionally substituted C2-C12alkynyl and optionally substituted C2-C12 heteroalkyl;
X is a linking moiety;
Y is a molecular recognition moiety, wherein the molecular recognition moiety is a molecular recognition portion of folic acid;
or a pharmaceutically acceptable salt or complex thereof.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein X is a group of the formula
—(CH2)n—,
wherein optionally one or more of the CH2 groups may be independently replaced by a heteroatomic group selected from S, O, P and NR3 where R3 is selected from the group consisting of H, optionally substituted C1-C12alkyl, optionally substituted C3-C12cycloalkyl, optionally substituted C6-C18aryl, and optionally substituted C1-C18heteroaryl;
n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.

### Claim 3 (depends on 2)

A compound according to claim 2, wherein X is selected from the group consisting of —CH2—, —CH2CH2—, —CH2CH2CH2—, —CH2CH2CH2CH2— and —CH2OCH2—.

### Claim 4 (depends on 1)

A compound according to claim 1, wherein L is a macrocyclic metal ligand of the formula:
wherein each Rx and Ry are independently selected from the group consisting of H, CH3, CO2H, NO2, CH2OH, H2PO4, HSO3, CN, CONH2 and CHO;
each p is independently an integer selected from the group consisting of 2, 3, and 4.

### Claim 5 (depends on 1)

A compound according to claim 1, wherein Y1 is OH.

### Claim 6 (depends on 1)

A compound according to claim 1, wherein Y is OH.

### Claim 7 (depends on 1)

A compound according to claim 1, wherein the nitrogen-containing macrocyclic metal ligand is coordinated with a metal ion.

### Claim 8 (depends on 7)

A compound according to claim 7, wherein the metal ion is a radionuclide selected from the group consisting of Cu, Tc, Gd, Ga, In, Co, Re, Fe, Au, Ag, Rh, Pt, Bi, Cr, W, Ni, V, Ir, Pt, Zn, Cd, Mn, Ru, Pd, Hg, and Ti.

### Claim 9 (depends on 8)

A compound according to claim 8, wherein the metal ion is a radionuclide selected from the group consisting of 60Cu, 62Cu, 64Cu and 67Cu.

### Claim 10 (depends on 1)

A pharmaceutical composition comprising a compound according to claim 1.